Despite remarkable recent advances in therapeutics, rheumatoid arthritis still represents an unmet medical need. Hence, there is an urgent need to develop and test new biocompatible, long-acting and safe biological response modifiers for patients with this condition. To this end, the focus of this exploratory/development research project is on determining the efficacy and safety of an innovative strategy developed in our laboratory consisting of homing low dose VIP to injured joints in rheumatoid arthritis. Our approach exploits the endowed biophysical properties of VIP to self-associate with biocompatible and biodegradable phospholipid nanoparticles (average size, approximately 17 rim) composed of distearoylphosphatidylethanolamine- poly-(ethylene)glycol (PEG; Mr, 2000 (DSPE-PEG2000) that form sterically stabilized micelles. These interactions lead to conformational transition of the VIP molecule from a predominantly random coil in aqueous solution to alpha-helix, the preferred and most stable conformation for ligand-receptor interactions, in the presence of micelles. This process protects VIP from degradation and inactivation in biological fluids and prolongs its circulation time because the PEG molecules grafted on the surface of micelles confer steric hindrance thereby evading uptake by the reticuloendothelial system. Consequently, the dose of VIP required to achieve its intended biological effect is reduced appreciably as are adverse events relative to a similar nominal dose of the unstable VIP monomers. Importantly, the salutary effects of VIP-containing nanoparticles are amplified because they selectively extravasate from the leaky microcirculation of injured tissues into the interstitial space and subsequently bind to VIP receptors overexpressed on the surface of immune and inflammatory effectors cells in these tissues. This active targeting process is amplified by the absence of VIP receptors on the luminal side of microvascular endothelial cells. On aggregate, these attributes indicate that micellar VIP could represent a novel, biocompatible, long-acting and safe targeted disease-modifying drug for patients with rheumatoid arthritis. The purpose this study is to determine whether intravenous or subcutaneous administration of low dose micellar VIP abates collagen-induced arthritis in mice without affecting systemic arterial pressure. The basic tenet of this proposal is that low dose micellar VIP is actively targeted to injured joints where it downregulates certain key tissue injury-promoting cytokines and matrix proteinases while up-regulating certain key tissue repair-promoting cytokines elaborated by activated effector cells in injured joints of mice with collagen-induced arthritis. This, in turn, will shift the balance of the immune and inflammatory cascades toward tissue repair. The specific aims are: 1) Optimize the formulation of micellar VIP for in vivo administration; 2) Determine the efficacy and safety of intravenous or subcutaneous micellar VIP in mice with collagen-induced arthritis; 3) Determine the effects of intravenous or subcutaneous micellar VIP on circulating biomarkers of tissue injury and repair in mice with collagen-induced arthritis; and 4) Determine the pharmacokinetics and biodistribution of intravenous or subcutaneous micellar 125I-VIP in mice with collagen-induced arthritis. The anticipated results of the proposed studies will provide proof of principle and set the stage for testing micellar VIP as a novel, safe, long-acting and efficacious disease modifying drug in patients with rheumatoid arthritis.